This is a research program devoted to understanding the fundamental molecular processes by which hallucinogens and other agents associated with drugs of abuse act on the receptors through which they elicit their pharmacological responses. The goal of the work proposed in this application is to refine the understanding of the structural basis for the action of hallucinogens on receptors of the neurotransmitter serotonin (5- hydroxytryptamine; 5-HT), and to develop the approaches necessary to use this newly gained understanding in the design of novel compounds with selective properties as agonists, partial agonists and antagonists on the receptors shared by hallucinogens and other 5-HT receptor ligands. Such compounds should provide new tools for the investigation of the complex and multifacted actions of hallucinogenic compounds, and offer the promise for new therapeutic and preventive modalities. The proposal focuses on the 5- HT1A receptors, developed in preliminary studies on the basis of computational simulations of drug-receptor interactions in a model receptor protein, will be calibrated and refined with specific attention to the actions of compounds belonging to the chemical classes of known hallucinogens. Effects of the ligands on the receptor activation mechanism (a specific proton transfer), will be calculated with a combination of computational methods with quantum chemistry and molecular dynamics. The studies of receptor activation will include the dynamic properties of the macromolecular environment, in order to account for the selectivity of the recognition process, and to simulate the effect of ligand binding and proton transfer on the macromolecular receptor environment. The proposed mechanisms will be scrutinized against processes feasible within the structures of other proteins, including the authentic receptor. Analysis will concentrate on the structural correlates of properties which affect the energetics of the proton transfer in receptor activation. The results scales of efficacy measured experimentally in collaborative studies. The validity and applicability of such correlates will thus be probed theoretically as well as experimentally (with collaborators, on tryptamine derivatives, ergolines, and derivatives of phenethylamine and phenylisopropylamine), and tested by predictions of new molecular structures of ligands that will be selective, and possess a predicted efficacy. Following similar protocols, mechanisms at 5-HT2 receptor will be explored with a working hypothesis that the ligands interact by stacking with a residue of an aromatic amino acid. Short peptide sequences from proteins which have been shown to bind 5-HT, including myelin basic protein, LHRH and MSH-ACTH will serve as first models of recognition sites. Mechanisms at 5-HT1A and 5-HT2 receptors will be compared for pairs such as d-LSD vs. lisuride, 5-HT vs psilocyn (or bufotenine), LSD vs. DOI or DOB.